Combinations od dipeptidyl peptidase iv inhibitors and other antidiabetic agents for the treatment of diabetes mellitus

ABSTRACT

A method for the treatment of diabetes mellitus, especially Type 2 diabetes and conditions associated with diabetes mellitus in a mammal such as a human, which method comprises administering an effective, non-toxic and pharmaceutically acceptable amount of a dipeptidyl peptidase IV inhibitor and another antidiabetic agent, to a mammal in need thereof.

[0001] This invention relates to a method of treatment, in particular toa method for the treatment of diabetes mellitus, especially non-insulindependent diabetes (NIDDM) or Type 2 diabetes and conditions associatedwith diabetes mellitus and to compositions for use in such method.

[0002] Dipeptidyl peptidase IV (DPP-IV) is a post-proline/alaninecleaving serine protease found in various tissues of the body includingkidney, liver, and intestine.

[0003] It is known that DPP-IV inhibitorsare may be useful for thetreatment of impaired glucose tolerance and diabetes mellitus(International Patent Application, Publication Number WO99/61431,Pederson R A et al,.Diabetes. August 1998;47(8):1253-8 and Pauly R P etal, Metabolism March 1999;48(3):385-9). In particular WO99/61431discloses DPP-IV inhibitors comprising an amino acid and a thiazolidineor pyrrolidine group, and salts thereof, such as isoleucyl (orisoleucine) thiazolidide and salts thereof.

[0004] Other DPP-IV inhibitors include those disclosed in U.S. Pat. No.6,124,305 and U.S. Pat. No. 6,107,317, International PatentApplications, Publication Numbers WO 9819998, WO 9515309 and WO 9818763.

[0005] Alpha glucosidase inhibitor antihyperglycaemic agents (or alphaglucosidase inhibitors) and biguanide antihyperglycaemic agents (orbiguanides) are commonly used in the treatment of Type 2 diabetes.Acarbose, voglibose, emiglitate and miglitol are examples of alphaglucosidase inhibitors. 1,1-Dimethylbiguanidine (or metformin) is aparticular example of a biguanide.

[0006] Insulin secretagogues are compounds that promote increasedsecretion of insulin by the pancreatic beta cells. The sulphonylureasare well known examples of insulin secretagogues. The sulphonylureas actas hypoglycaemic agents and are used in the treatment of Type 2diabetes. Examples of sulphonylureas include glibenclamide (orglyburide), glipizide, gliclazide, glimepiride, tolazamide andtolbutamide.

[0007] European Patent Application, Publication Number 0,306,228 relatesto certain thiazolidinedione derivatives disclosed as havingantihyperglycaemic and hypolipidaemic activity. One particularthiazolidinedione disclosed in EP 0306228 is5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione(hereinafter ‘Compound (I)’). WO94/05659 discloses certain salts ofCompound (I) including the maleate salt at example 1 thereof.

[0008] Compound (I) is an example of a class of anti-hyperglycaemicagents known as ‘insulin sensitisers’. In particular Compound (I) is athiaiolidinedione insulin sensitiser. Compound (I) is also a peroxisomeproliferator-activated receptor (PPARγ) agonist insulin sensitiser.

[0009] European Patent Applications, Publication Numbers: 0008203,0139421, 0032128, 0428312, 0489663, 0155845, 0257781, 0208420, 0177353,0319189, 0332331, 0332332, 0528734, 0508740; International PatentApplication, Publication Numbers 92/18501, 93/02079, 93/22445 and U.S.Pat. Nos. 5,104,888 and 5,478,852, also disclose certainthiazolidinedione insulin sensitisers.

[0010] Another series of compounds generally recognised as havinginsulin sensitiser activity are those typified by the compoundsdisclosed in International Patent Applications, Publication NumbersWO093/21166 and WO94/01420. These compounds are herein referred to as‘acyclic insulin sensitisers’. Other examples of acyclic insulinsensitisers are those disclosed in U.S. Pat. No. 5,232,945 andInternational Patent Applications, Publication Numbers WO92/03425 andWO91/19702.

[0011] Examples of other insulin sensitisers are those disclosed inEuropean Patent Application, Publication Number 0533933, Japanese PatentApplication Publication Number 05271204 and U.S. Pat. No. 5,264,451.

[0012] The above mentioned publications are incorporated herein byreference.

[0013] It is now indicated that dipeptidyl peptidase IV inhibitors, suchas the compounds of WO99/61431, in combination with other antidiabeticagents provide a particularly beneficial effect on glycaemic control andthat such combination is therefore suggested to be particularly usefulfor the treatment of diabetes mellitus, especially Type 2 diabetes andconditions associated with diabetes mellitus. Such combinations willprovide improved blood glucose regulation without introducingunacceptable side-effects.

[0014] Accordingly, the invention provides a method for the treatment ofdiabetes mellitus, especially Type 2 diabetes and conditions associatedwith diabetes mellitus in a mammal such as a human, which methodcomprises administering an effective, non-toxic and pharmaceuticallyacceptable amount of a dipeptidyl peptidase IV inhibitor and anotherantidiabetic agent, to a mammal in need thereof.

[0015] In another aspect the invention provides a dipeptidyl peptidaseIV inhibitor and another antidiabetic agent, for use in a method for thetreatment of diabetes mellitus, especially Type 2 diabetes andconditions associated with diabetes mellitus.

[0016] The method comprises either co-administration of a dipeptidylpeptidase IV inhibitor and another antidiabetic agent or the sequentialadministration thereof.

[0017] Co-administration includes administration of a formulation whichincludes both a DPP-IV inhibitor and the other antidiabetic agent or theessentially simultaneous administration of separate formulations of eachagent.

[0018] In another aspect the invention provides the use of a dipeptidylpeptidase IV inhibitor and another antidiabetic agent for use in themanufacture of a composition for the treatment of obesity, diabetesmellitus, especially Type 2 diabetes and conditions associated withdiabetes mellitus.

[0019] Suitably, the other antidiabetic agent comprises one or more,generally one or two, of an alpha glucosidase inhibitor, a biguanide, aninsulin secretagogue or an insulin sensitiser.

[0020] Suitably, the other antidiabetic agent is selected from an alphaglucosidase inhibitor, a biguanide, an insulin secretagogue or aninsulin sensitiser.

[0021] A further suitable antidiabetic agent is insulin.

[0022] A suitable alpha glucosidase inhibitor is acarbose.

[0023] Other suitable alpha glucosidase inhibitors are emiglitate andmiglitol. A further suitable alpha glucosidase inhibitor is voglibose.

[0024] Suitable biguanides include metformin, buformin or phenformin,especially metformin.

[0025] Suitable insulin secretagogues include sulphonylureas.

[0026] Suitable sulphonylureas include glibenclamide, glipizide,gliclazide, glimepiride, tolazamide and tolbutamide. Furthersulphonylureas include acetohexamide, carbutamide, chlorpropamide,glibomuride, gliquidone, glisentide, glisolamide, glisoxepide,glyclopyamide and glycylamide. Also included is the sulphonylureaglipentide.

[0027] A further suitable insulin secretagogue is repaglinide. Anadditional insulin secretagogue is nateglinide.

[0028] Insulin sensitisers include PPARγ agonist insulin sensitisersincluding the compounds disclosed in WO 97/31907 and especially2-(1-carboxy-2-{4-{2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}-ethylamino)-benzoicacid methyl ester and2(S)-(2-benzoyl-phenylamino)-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}-propionicacid.

[0029] Insulin sensitisers also include thiazolidinedione insulinsensitisers.

[0030] A preferred insulin sensitiser is Compound (I) or a derivativethereof.

[0031] Other suitable thiazolidinedione insulin sensitisers include (+)-5-[[4-[(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-yl)methoxy]phenyl]methyl]-2,4-thiazolidinedione(or troglitazone),5-[4-[(1-methylcyclohexyl)methoxy]benzyl]thiazolidine-2,4-dione (orciglitazone),5-[4-[2-(5-ethylpyridin-2-yl)ethoxy]benzyl]thiazolidine-2,4-dione (orpioglitazone) or5-[(2-benzyl-2,3-dihydrobenzopyran)-5-ylmethyl)thiazolidine-2,4-dione(or englitazone).

[0032] A particular thiazolidinedione insulin sensitiser is5-[4-[2-(5-ethylpyridin-2-yl)ethoxy]benzyl]thiazolidine-2,4-dione (orpioglitazone).

[0033] A particular thiazolidinedione insulin sensitiser is (+)-5-[[4-[(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-yl)methoxy]phenyl]methyl]-2,4-thiazolidinedione(or troglitazone).

[0034] Particular DPP-IV inhibitors include the specific examplesdisclosed in WO99/61431, such as L-threo-isoleucyl pyrrolidide,L-allo-isoleucyl thiazolidide, L-allo-isoleucyl pyrrolidide and saltsthereof. A particular DPP-IV inhibitor is isoleucine thiazolidide andsalts thereof.

[0035] Further DPP-IV inhibitors include the specific examples disclosedin U.S. Pat. No. 6,124,305 and U.S. Pat. No. 6,107,317, InternationalPatent Applications, Publication Numbers WO 9819998, WO 9515309 and WO9818763; such as1[2-[(5-cyanopyridin-2-yl)aminoethylamino]acetyl-2-cyano-(S)-pyrrolidineand(2S)-1-[(2S)-2-amino-3,3-dimethylbutanoyl]-2-pyrrolidinecarbonitrile.

[0036] For the avoidance of doubt, the examples disclosed in each of theabove mentioned publications are specifically incorporated herein byreference, as individually disclosed compounds.

[0037] It will be understood that the DPP-IV inhibitor and the otherantidabetic agent are each administered in a pharmaceutically acceptableform, including pharmaceutically acceptable derivatives such aspharmaceutically acceptable salts, esters and solvates thereof, asappropriate of the relevant pharmaceutically active agent. In certaininstances herein the names used for the other antidabetic agent mayrelate to a particular pharmaceutical form of the relevant active agent:It will be understood that all pharmaceutically acceptable forms of theactive agents per se are encompassed by this invention.

[0038] Suitable pharmaceutically acceptable forms of the otherantidiabetic agent depend upon the particular agent being used butinclude known pharmaceutically acceptable forms of the particular agentchosen. Such derivatives are found or are referred to in standardreference texts such as the British and US Pharmacopoeias, Remington'sPharmaceutical Sciences (Mack Publishing Co.), Martindale The ExtraPharmacopoeia (London, The Pharmaceutical Press) (for example see the31st Edition page 341 and pages cited therein) or the above mentionedpublications.

[0039] Suitable pharmaceutically acceptable forms of the DPP-IVinhibitor include salted forms and solvated forms, include thosedescribed in WO 99/61431, for example the fumarate salt

[0040] The DPP-IV inhibitor is prepared according to published methods,for example when the DPP-IV inhibitor is a compound of WO 99/61431 or aderivative thereof such as a pharmaceutically acceptable salt thereof ora pharmaceutically acceptable solvate thereof, then it is preparedaccording to methods disclosed therein. Similarly for the compounds ofU.S. Pat. No. 6,124,305 and U.S. Pat. No. 6,107,317 and those ofInternational Patent Applications, Publication Numbers WO 9819998, WO9515309 and WO 9818763.

[0041] Certain of the compounds mentioned herein may contain one or morechiral carbon atoms and hence can exist in two or more isomeric forms,all of which are encompassed by the invention, either as individualisomers or as mixtures of isomers, including racemates. Certain of thecompounds mentioned herein, in particular the thiazolidinediones such asCompound (I), may exist in one of several tautomeric forms, all of whichare encompassed by the invention as individual tautomeric forms or asmixtures thereof

[0042] The DPP-IV inhibitor and the other antidiabetic agent of choiceis prepared according to known methods, such methods are found or arereferred to in standard reference texts, such as the British and USPharmacopoeias, Remington's Pharmaceutical Sciences (Mack PublishingCo.), Martindale The Extra Pharmacopoeia (London, The PharmaceuticalPress) (for example see the 31st Edition page 341 and pages citedtherein) or the above mentioned publications.

[0043] When used herein the term ‘conditions associated with diabetes’includes those conditions associated with the pre-diabetic state,conditions associated with diabetes mellitus itself and complicationsassociated with diabetes mellitus.

[0044] When used herein the term ‘conditions associated with thepre-diabetic state’ includes conditions such as insulin resistance,including hereditary insulin resistance, impaired glucose tolerance andhyperinsulinaemia.

[0045] ‘Conditions associated with diabetes mellitus itself’ includehyperglycaemia, insulin resistance, including acquired insulinresistance and obesity. Further conditions associated with diabetesmellitus itself include hypertension and cardiovascular disease,especially atherosclerosis and conditions associated with insulinresistance. Conditions associated with insulin resistance includepolycystic ovarian syndrome and steroid induced insulin resistance andgestational diabetes.

[0046] ‘Complications associated with diabetes mellitus’ includes renaldisease, especially renal disease associated with Type 2 diabetes,neuropathy and retinopathy.

[0047] Renal diseases associated with Type 2 diabetes includenephropathy, glomerulonephritis, glomerular sclerosis, nephroticsyndrome, hypertensive nephrosclerosis and end stage renal disease.

[0048] As used herein the term ‘pharmaceutically acceptable’ embracesboth human and veterinary use: for example the term ‘pharmaceuticallyacceptable’ embraces a veterinarily acceptable compound.

[0049] Diabetes mellitus is preferably Type 2 diabetes.

[0050] Suitably, the particularly beneficial effect on glycaemic controlprovided by the treatment of the invention is an improved therapeuticratio for the combination of the invention relative to the therapeuticratio for one compound of the combination when used alone and at a doseproviding an equivalent efficacy to the combination of the invention.

[0051] In a preferred aspect, the particularly beneficial effect onglycaemic control provided by the treatment of the invention isindicated to be a synergistic effect relative to the control expectedfrom the effects of the individual active agents.

[0052] In a further aspect of the invention, combining doses of theDPP-IV inhibitor and the other agent will produce a greater beneficialeffect than can be achieved for either agent alone at a dose twice thatused for that agent in the combination.

[0053] Glycaemic control may be characterised using conventionalmethods, for example by measurement of a typically used index ofglycaemic control such as fasting plasma glucose or glycosylatedhaemoglobin (Hb Alc). Such indices are determined using standardmethodology, for example those described in: Tuescher A, Richterich, P.,Schweiz. med. Wschr. 101 (1971), 345 and 390 and Frank P., ‘Monitoringthe Diabetic Patent with Glycosolated Hemoglobin Measurements’, ClinicalProducts 1988.

[0054] In a preferred aspect, the dosage level of each of the activeagents when used in accordance with the treatment of the invention willbe less than would have been required from a purely additive effect uponglycaemic control.

[0055] It is also considered that the treatment of the invention willeffect an improvement, relative to the individual agents, in the levelsof advanced glycosylation end products (AGEs), and serum lipidsincluding total cholesterol, HDL-cholesterol, LDL-cholesterol includingimprovements in the ratios thereof, in particular an improvement inserum lipids including total cholesterol, HDL-cholesterol,LDL-cholesterol including improvements in the ratios thereof.

[0056] In the treatment of the invention, the active medicaments arepreferably administered in pharmaceutical composition form. As indicatedabove, such compositions can include both medicaments or one only of themedicaments.

[0057] Accordingly, in one aspect the present invention also provides apharmaceutical composition comprising a dipeptidyl peptidase IVinhibitor and another antidiabetic agent and a pharmaceuticallyacceptable carrier therefor.

[0058] Thus, in a further aspect, the invention also provides a processfor preparing a pharmaceutical composition comprising a dipeptidylpeptidase IV inhibitor, another antidiabetic agent and apharmaceutically acceptable carrier therefor, which process comprisesadmixing the dipeptidyl peptidase IV inhibitor, another antidiabeticagent and a pharmaceutically acceptable carrier.

[0059] The compositions are preferably in a unit dosage form in anamount appropriate for the relevant daily dosage.

[0060] Suitable dosages, including especially unit dosages, of theDPP-IV inhibitor or the other antidiabetic agent include the knowndosages including unit doses for these compounds as described orreferred to in reference text such as the British and US Pharmacopoeias,Remington's Pharmaceutical Sciences (Mack Publishing Co.), MartindaleThe Extra Pharmacopoeia (London, The Pharmaceutical Press) (for examplesee the 31st Edition page 341 and pages cited therein) or the abovementioned publications.

[0061] Thus, suitable dosages for the DPP-IV inhibitors of WO 99/61431and include those disclosed therein, for example 0.01 to 30 mg per dayor 0.01 to 10 mg per kilogram of body weight. Also, the suitable dosesof the other DPP-IV inhibitors mentioned herein include those mentionedin the relevant publications mentioned above.

[0062] For the alpha glucosidase inhibitor, a suitable amount ofacarbose is in the range of from 25 to 600 mg, including 50 to 600 mg,for example 100 mg or 200 mg.

[0063] For the biguanide, a suitable dosage of metformin is between 100to 3000 mg, for example 250, 500 mg, 850 mg or 1000 mg.

[0064] For the insulin secretagogue, a suitable amount of glibenclamideis in the range of from 2.5 to 20 mg, for example 10 mg or 20 mg; asuitable amount of glipizide is in the range of from 2.5 to 40 mg; asuitable amount of gliclazide is in the range of from 40 to 320 mg; asuitable amount of tolazamide is in the range of from 100 to 1000 mg; asuitable amount of tolbutamide is in the range of from 1000 to 3000 mg;a suitable amount of chlorpropamide is in the range of from 100 to 500mg; and a suitable amount of gliquidone is in the range of from 15 to180 mg. Also a suitable amount of glimepiride is 1 to 6 mg and asuitable amount of glipentide is 2.5 to 20 mg.

[0065] A suitable amount of repaglinide is in the range of from 0.5 mgto 20 mg, for example 16 mg. Also a suitable amount of nateglinide is 90to 360 mg, for example 270 mg.

[0066] In one particular aspect, the composition comprises 2 to 12 mg ofCompound (I).

[0067] Suitably the composition comprises 2, 3, 4, 5, 6, 7, 8, 9, 10, 11or 12 mg of Compound (I).

[0068] Particularly, the composition comprises 2 to 4, 4 to 8 or 8 to 12mg of Compound (I).

[0069] Particularly, the composition comprises 2 to 4 mg of Compound(I).

[0070] Particularly, the composition comprises 4 to 8 mg of Compound(I).

[0071] Particularly, the composition comprises 8 to 12 mg of Compound(I).

[0072] Preferably, the composition comprises 2 mg of Compound (1).

[0073] Preferably, the composition comprises 4 mg of Compound (I).

[0074] Preferably, the composition comprises 8 mg of Compound (I).

[0075] Suitable unit dosages of other insulin sensitisers include from100 to 800 mg of troglitazone such as 200, 400, 600 or 800 mg or from 5to 50 mg, including 10 to 40 mg, of pioglitazone, such as 20, 30 or 40mg and also including 15, 30 and 45 mg of pioglitazone.

[0076] Suitable dosages of other PPARγ agonist insulin sensitisersinclude those disclosed for the respective agonist in the abovementionedapplications, for example2-(1-carboxy-2-{4-{2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}-ethylamino)-benzoicacid methyl ester and2(S)-(2-benzoyl-phenylamino)-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}-propionicacid are suitably dosed in accordance with the dosages disclosed in WO97/31907.

[0077] In the treatment the medicaments may be administered from 1 to 6times a day, but most preferably 1 or 2 times per day.

[0078] Also, the dosages of each particular active agent in any givencomposition can as required vary within a range of doses known to berequired in respect of accepted dosage regimens for that compound.Dosages of each active agent can also be adapted as required to takeinto account advantageous effects of combining the agents as mentionedherein.

[0079] It will be understood that the DPP-IV inhibitor and the otherantidiabetic agent are in a pharmaceutically acceptable form, includingpharmaceutically acceptable derivatives such as pharmaceuticallyacceptable salts, esters and solvates thereof, as appropriate to therelevant pharmaceutically active agent chosen. In certain instancesherein the names used for the antidiabetic agent may relate to aparticular pharmaceutical form of the relevant active agent: It will beunderstood that all pharmaceutically acceptable forms of the activeagents per se are encompassed by this invention.

[0080] The present invention also provides a pharmaceutical compositioncomprising a dipeptidyl peptidase IV inhibitor, another antidiabeticagent and a pharmaceutically acceptable carrier therefor, for use as anactive therapeutic substance.

[0081] In particular, the present invention provides a pharmaceuticalcomposition comprising a dipeptidyl peptidase IV inhibitor, anotherantidiabetic agent and a pharmaceutically acceptable carrier therefor,for use in the treatment of diabetes mellitus, especially Type 2diabetes and conditions associated with diabetes mellitus.

[0082] Usually the compositions are adapted for oral administration.However, they may be adapted for other modes of administration, forexample parenteral administration, sublingual or transdermaladministration.

[0083] The compositions may be in the form of tablets, capsules,powders, granules, lozenges, suppositories, reconstitutable powders, orliquid preparations, such as oral or sterile parenteral solutions orsuspensions.

[0084] In order to obtain consistency of administration it is preferredthat a composition of the invention is in the form of a unit dose.

[0085] Unit dosage presentation forms for oral administration may be intablet or capsule form and may as necessary contain conventionalexcipients such as binding agents, fillers, lubricants, glidants,disintegrants and wetting agents.

[0086] The solid oral compositions may be prepared by conventionalmethods of blending, filling or tabletting. Repeated blending operationsmay be used to distribute the active agent throughout those compositionsemploying large quantities of fillers. Such operations are of courseconventional in the art. The tablets may be coated according to methodswell known in normal pharmaceutical practice, in particular with anenteric coating.

[0087] Oral liquid preparations may be in the form of, for example,emulsions, syrups, or elixirs, or may be presented as a dry product forreconstitution with water or other suitable vehicle before use. Suchliquid preparations may contain conventional additives such assuspending agents, for example sorbitol, syrup, methyl cellulose,gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminiumstearate gel, hydrogenated edible fats; emulsifying agents, for examplelecithin, sorbitan monooleate, or acacia; non-aqueous vehicles (whichmay include edible oils), for example almond oil, fractionated coconutoil, oily esters such as esters of glycerine, propylene glycol, or ethylalcohol; preservatives, for example methyl or propyl p-hydroxybenzoateor sorbic acid; and if desired conventional flavouring or colouringagents.

[0088] For parenteral administration, fluid unit dosage forms areprepared utilizing the compound and a sterile vehicle, and, depending onthe concentration used, can be either suspended or dissolved in thevehicle. In preparing solutions the compound can be dissolved in waterfor injection and filter sterilized before filling into a suitable vialor ampoule and sealing. Advantageously, adjuvants such as a localanaesthetic, a preservative and buffering agent can be dissolved in thevehicle. To enhance the stability, the composition can be frozen afterfilling into the vial and the water removed under vacuum. Parenteralsuspensions are prepared in substantially the same manner, except thatthe active compound is suspended in the vehicle instead of beingdissolved, and sterilization cannot be accomplished by filtration. Thecompound can be sterilized by exposure to ethylene oxide beforesuspending in the sterile vehicle. Advantageously, a surfactant orwetting agent is included in the composition to facilitate uniformdistribution of the compound.

[0089] Compositions may contain from 0.1% to 99% by weight, preferablyfrom 10-60% by weight, of the active material, depending upon the methodof administration.

[0090] Examples of binding agents include acacia, alginic acid,carboxymethylcellulose calcium, carboxymethylcellulose sodium,dextrates, dextrin, dextrose, ethylcellulose, gelatin, liquid glucose,guar gum, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethylcellulose, magnesium aluminium silicate, maltodextrin, methylcellulose, polymethacrylates, polyvinylpyrrolidone, pregelatinisedstarch, sodium alginate, sorbitol, starch, syrup, tragacanth.

[0091] Examples of fillers include calcium carbonate, calcium phosphate,calcium sulphate, carboxymethylcellulose calcium, carboxymethylcellulosesodium, compressible sugar, confectioner's sugar, dextrates, dextrin,dextrose, dibasic calcium phosphate dihydrate, dibasic calciumphosphate, fructose, glyceryl palmitostearate, glycine, hydrogenatedvegetable oil-type 1, kaolin, lactose, maize starch, magnesiumcarbonate, magnesium oxide, maltodextrin, mannitol, microcrystallinecellulose, polymethacrylates, potassium chloride, powdered cellulose,pregelatinised starch, sodium chloride, sorbitol, starch, sucrose, sugarspheres, talc, tribasic calcium phosphate, xylitol.

[0092] Examples of lubricants include calcium stearate, glycerylmonostearate, glyceryl palmitostearate, magnesium stearate,microcrystalline cellulose, sodium benzoate, sodium chloride, sodiumlauryl sulphate, stearic acid, sodium stearyl fumarate, talc, zincstearate.

[0093] Examples of glidants include colloidal silicon dioxide, powderedcellulose, magnesium trisilicate, silicon dioxide, talc.

[0094] Examples of disintegrants include alginic acid,carboxymethylcellulose calcium, carboxymethylcellulose sodium, colloidalsilicon dioxide, croscarmellose sodium, crospovidone, guar gum,magnesium aluminium silicate, microcrystalline cellulose, methylcellulose, polyvinylpyrrolidone, polacrilin potassium, pregelatinisedstarch, sodium alginate, sodium lauryl sulphate, sodium starchglycollate.

[0095] An example of a pharmaceutically acceptable wetting agent issodium lauryl sulphate.

[0096] The compositions are prepared and formulated according toconventional methods, such as those disclosed in standard referencetexts, for example the British and US Pharmacopoeias, Remington'sPharmaceutical Sciences (Mack Publishing Co.), Martindale The ExtraPharmacopoeia (London, The Pharmaceutical Press) (for example see the31st Edition page 341 and pages cited therein) and Harry's Cosmeticology(Leonard Hill Books) or the above mentioned publications.

[0097] For example, the solid oral compositions may be prepared byconventional methods of blending, filling or tabletting. Repeatedblending operations may be used to distribute the active agentthroughout those compositions employing large quantities of fillers.Such operations are of course conventional in the art. The tablets maybe coated according to methods well known in normal pharmaceuticalpractice.

[0098] Compositions may, if desired, be in the form of a packaccompanied by written or printed instructions for use.

[0099] No adverse toxicological effects are expected for thecompositions or methods of the invention in the above mentioned dosageranges.

[0100] Pharmacological Data

[0101] Age and weight matched male ZDF fa/fa rats (Genetic Models, Inc.,Indianapolis, Ind.) were housed individually at 72° F. and 50% relativehumidity with a 12 h light/dark cycle and fed PMI 5008 Formulab Diet(PMI Nutrition International, Saint Louis, Mo.).

[0102] Animals were dosed by oral gavage twice daily during the darkcycle for one week with vehicle (0.5% hydroxy-propylmethylcellulose(HPMC) plus 0.1% Tween 80), 100 mg/kg isoleucine thiazolidide (Compound(II)), 5 mg/kg Compound (I) in vehicle, or 5 mg/kg Compound (1) plus 100mg/kg Compound (II) in vehicle.

[0103] For glucose tolerance measurements, rats were treated with testcompound for 7 days and given an intraperitoneal injection of a glucosesolution in saline 30 minutes after the last dose of test compound.

[0104] Rats were anesthetized with isofluorane for cardiac bloodcollection 30 minutes after administraion of the glucose solution. Serumchemistry measurements were obtained using an automated chemistryanalyzer (ILab600, Instrument Laboratory, Lexington, Mass.).

[0105] DPP-IV activity was measured using the fluorogenic substrateGly-Pro-AMC (50 mM) according to the manufacturers specification (EnzymeSystem Products, Livermore Calif.). The substrate was mixed with 50 mMTris, pH 7.8, in plasma (20% final v/v) and the samples were incubatedfor 5-20 min at 30° C. DPP-IV activity was determined by measuringfluorescence using a cytofluor spectrofluoremeter with the filters setat 360 nm excitation and 460 nm emission.

[0106] Results from each group (n=6) were averaged and compared tovehicle treated rats to determine significance and are shown in Table I.

[0107] The following data illustates the invention but does not limit itin any way. TABLE I ZDF rats, treated BID for 7 days Plasma % HbA1CPlasma Glucose DPP-IV activity (7 day change) (30 min GTT) Control 5544± 485 1.63 ± 1.12 695 ± 24 Compound (I) 4104 ± 399* 0.79 ± 0.54* 665 ±40 (5 mg/kg) Compound (II)  962 ± 53* 1.81 ± 1.24 684 ± 60 (100 mg/kg)Combination  703 ± 16* 0.41 ± 0.28* 454 ± 52*

1. A method for the treatment of diabetes mellitus, especially Type 2diabetes and conditions associated with diabetes mellitus in a mammalsuch as a human, which method comprises administering an effective,non-toxic and pharmaceutically acceptable amount of a dipeptidylpeptidase IV inhibitor and another antidiabetic agent, to a mammal inneed thereof.
 2. A method according to claim 1, wherein the dipeptidylpeptidase IV is selected from: L-threo-isoleucyl pyrrolidide,L-allo-isoleucyl thiazolidide, L-allo-isoleucyl pyrrolidide; and saltsthereof or1[2-[(5-cyanopyridin-2-yl)aminoethylamino]acetyl-2-cyano-(S)-pyrrolidineand(2S)-1-[(2S)-2-amino-3,3-dimethylbutanoyl]-2-pyrrolidinecarbonitrile. 3.A method according to claim 1 or claim 2, wherein the other antidiabeticagent comprises one or more of an alpha glucosidase inhibitor, abiguanide, an insulin secretagogue or an insulin sensitiser.
 3. A methodaccording to claim 3, wherein the alpha glucosidase inhibitor isselected from acarbose, emiglitate, miglitol and voglibose.
 4. A methodaccording to claim 3, wherein the biguanide is selected from metformin,buformin and phenformin.
 5. A method according to claim 3, wherein theinsulin secretagogue is a sulphonylurea selected from: glibenclamide,glipizide, gliclazide, glimepiride, tolazamide and tolbutamide,acetohexamide, carbutamide, chlorpropamide, glibornuride, gliquidone,glisentide, glisolamide, glisoxepide, glyclopyamide, glycylamide andglipentide.
 6. A method according to claim 3, wherein the insulinsecretagogue is repaglinide or nateglinide.
 7. A method according toclaim 3, wherein the insulin sensitiser is thiazolidinedione.
 8. Amethod according to claim 7, wherein the thiazolidinedione is selectedfrom: (+)-5-[[4-[(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-yl)methoxy]phenyl]methyl]-2,4-thiazolidinedione(or troglitazone),5-[4-[(1-methylcyclohexyl)methoxy]benzyl]thiazolidine-2,4-dione (orciglitazone),5-[4-[2-(5-ethylpyridin-2-yl)ethoxy]benzyl]thiazolidine-2,4-dione (orpioglitazone) or5-[(2-benzyl-2,3-dihydrobenzopyran)-5-ylmethyl)thiazolidine-2,4-dione(or englitazone).
 9. A method according to claim 7, wherein thethiazolidinedione is5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione,5-[4-[2-(5-ethylpyridin-2-yl)ethoxy]benzyl]thiazolidine-2,4-dione (orpioglitazone); or a pharmaceutically acceptable derivative thereof. 10.A pharmaceutical composition comprising a dipeptidyl peptidase IVinhibitor and another antidiabetic agent and a pharmaceuticallyacceptable carrier therefor.
 11. A process for preparing apharmaceutical composition comprising a dipeptidyl peptidase IVinhibitor, another antidiabetic agent and a pharmaceutically acceptablecarrier therefor, which process comprises admixing the dipeptidylpeptidase IV inhibitor, the other antidiabetic agent and apharmaceutically acceptable carrier.
 12. A pharmaceutical compositioncomprising a dipeptidyl peptidase IV inhibitor, another antidiabeticagent and a pharmaceutically acceptable carrier therefor, for use as anactive therapeutic substance.
 13. A pharmaceutical compositioncomprising a dipeptidyl peptidase IV inhibitor, another antidiabeticagent and a pharmaceutically acceptable carrier therefor, for use in thetreatment of diabetes mellitus, especially Type 2 diabetes andconditions associated with diabetes mellitus.